Use of KPV tripeptide for dermatological disorders

ABSTRACT

The present invention is directed to a prevention and treatment for dermatological disorders. One aspect of this invention involves a dermatological treatment comprising one or more polypeptides with an amino acid sequence including KPV (SEQ. ID. NO. 1), MEHFRWGKPV (SEQ. ID. NO. 2), HFRWGKPV (SEQ. ID. NO. 3), or SYSMEHFRWGKPV (SEQ. ID. NO. 4) for the treatment and prevention of dermatological disorders. The polypeptides are at a level to effectively treat the cutaneous inflammation and are carried by a carrier. The one or more polypeptides can also be a dimer formed from any of the amino acid sequence above.

RELATED APPLICATIONS

This application is a Divisional of U.S. application Ser. No. 09/828,272filed on Apr. 6, 2001, now U.S. Pat. No. 6,894,028 and which isincorporated by reference as if fully set forth herein, includingfigures and tables.

FIELD OF INVENTION

The present invention relates to a method of treating dermatologicaldisorders with formulations including a polypeptide having a KPV aminoacid sequence.

BACKGROUND OF INVENTION

The skin, also known as the integumentary system, is the largest organin the body. The skin is an organ with its own anatomy, physiology, andfunctions. For example, some of the integumentary system's functions areas a protection from the environment and microorganisms, as a sensorysystem, as a temperature control system, as an excretory system, andeven as a chemical factory in the production of vitamin D.Unfortunately, as with any organ that has its own anatomy andphysiology, comes pathology.

There are over 2000 disorders that can affect the integumentary system.Fitzpatrick, Polono, Suurmound, Color Atlas and Synopsis of ClinicalDermatology (1983). What separates the disorders of the integumentarysystem from other organs is that the symptoms of the disorders of theintegumentary system are so readily sensed and palpable to the oneafflicted and visible to that person and others. Additionally, themanifestations and symptoms of skin disorders are easily and immediatelyexacerbated by the sufferer of the disorder. For example, many of the2000 disorders of the skin manifest with lesions that carry with themthe symptoms of pruritis (“itching”), erythema (heat and redness), andalgesia (pain). A person trying to relieve the symptom of a skindisorder may make the condition worse by consciously or, even morecommonly, unconsciously scratching at lesions manifested by thedisorder. These differences, as well as many others, make the treatmentof skin ailments a unique and difficult problem.

Some of the more common and well-recognized diseases are the psoriaticdisorders and the specific abnormalities that fall within the class ofeczematous dermatitis. Psoriasis, for example, affects about threepercent of the world's population. See, Baker, Burton, Zieve, Principlesof Ambulatory Medicine, Williams and Wilkins (1982).

The psoriatic syndromes are related by a constellation of symptomsincluding pruritis, pain, visible lesions, inflammation, hair and nailchanges and, in up to 32% of the cases, debilitating arthritis. The skinlesions can be distributed as single lesions or lesions localized to onearea, or may be regional and generalized in a universal patternaffecting the integument as well as the skin appendages (hair andnails). The presentation is rarely symmetrical and favors areas offriction.

The pathophysiology of the syndromes includes a marked decrease inepidermal turnover time resulting in a markedly increased number ofmitotic cells in the dividing pool. This creates a vastly increasedepidermal proliferation. The epidermis and the dermis appear to respondas an integrated unit and show primary changes in the keratinocytes andkeratogenous zones of the epidermis and inflammatory changes in thedermis. The resulting lesions are located in an area of erythroderma andinclude papules and plaques with marked silvery-white scaling. Thepapules may become pustules upon contamination. See, Fitzpatrick, et al.Color Atlas and Synopsis of Clinical Dermatology McGraw Hill Book Co.(1983); Barker, Burton Zieve, Principles of Ambulatory Medicine,Williams & Wilkins, (1982).

Treatment for sufferers of psoriatic syndromes has been difficult.Treatment decisions are made considering the type of psoriasis, thestage of the disease, the site of involvement, the age of the patientand the degree of disability or disfigurement. It is well known thatmany treatments available must be curtailed or even removed fromconsideration depending on the factors mentioned above. For example,methotrexate, a highly toxic anti-metabolite and cytotoxic medicine,which is used in recalcitrant psoriasis, can be fatal to patients. Othermethods of treatment are time consuming, expensive, show poor patientcompliance and are poorly tolerated by many patients. These include, butare not limited to, Psorelen Long Wave Ultra Violet Light, Retinoidtherapy, Tar, and intralesional injections of steroids (which are quitepainful). In cases with secondary fungal infection, ketoconazole(Nizoral®), a very common and popular antifungal, is used. Ketoconazole,however, has serious side effects which may be fatal when combined withterfenadine; known by the public as Seldane® (a commonly used allergymedication).

Avoidance of these complications presents a welcome invitation to a newpreparation that is well tolerated by a number of people suffering frompsoriasis. As will be described below, α-MSH and/or its derivatives showefficacy in these areas.

Another area of dermatological abnormalities that show a positiveresponse to α-MSH and/or its derivatives are the delayedhypersensitivity reactions, i.e. allergic contact dermatitis (an examplewould be a reaction from an exposure to poison ivy) and primary irritantcontact dermatitis (an example would be a reaction from repeatedexposure to certain substances to which a person may be hypersensitive).

Similar to psoriasis, and most of the dermatological disorders, contactdermatitis shows a constellation of integumentary changes. Among theseare irregular and poorly outlined patches of erythema and edema,vesicles, erosions exuding serum, and crusts. In chronic forms ofcontact dermatitis, a person may suffer patches of lichenification(thickening of the epidermis with deepening of the skin lines inparallel or rhomboidal pattern), hyperpigmentation and scaring fromexcoriation.

Early and tolerated treatment is of a great benefit to people sufferingfrom contact dermatitis. Unfortunately, the stan dby treatment is,again, antihistamines and steroids; oral and topical, i.e. oral in theacute phase and topical in the subacute and chronic phase. Although thesteroids function well in reduction of symptoms, they share the samedrawbacks as listed above. Additionally, steroids would not be used in aprophylactic way due to their list of adverse side effects. A medicationis needed that survives both as a symptomatic treatment as well as apreventative one. This medication would have applications in many of thediseases listed as well as others with just as complicated nomenclatureand pathophysiology.

Regardless of the difficult nomenclature, however, many diseases of theintegumentary system share the same pathophysiology and, therefore,share similar symptoms and sequelae. Of these symptoms, inflammation,algisia and pruritis are the most common, and it is these symptoms towhich physicians direct their attention in the empirical treatment ofskin disease. As with the diseases mentioned above, the overwhelmingfirst line of treatment for physicians treating skin disease, especiallynon-specialists in the area, is some preparation of a steroid-basedmedicine. Hydrocortisone, betamethasone and prednisolone are commonlyused steroids in many prescription and over-the-counter preparations ofanti-inflammatory and anti-pruritic topical preparations. Often aphysician will use an antihistamine in addition to, or as an alternativefor, steroid therapy to control the effects of vascular permeabilitythat is the result of the release of histamine from mast cells in theprimary stages of inflammation. See, Ryan and Majano, Inflammation, aScope Publication, The Upjohn Company, (1977).

Although the use of topical steroids and antihistamines are useful, theycarry with them a long history of well-established and unwanted sideeffects. For example, antihistamines cause drowsiness and can be poorlytolerated in many individuals. Topical steroids are known to createproblems for the integument that may be worse than the lesion they wereintended to ameliorate. Here, the treatment may be worse than thedisease.

For example, topical steroid use for as little as two weeks cancause: 1) telangiectasia (dilation of capillaries and sometimes ofterminal arteries producing an angioma of macular appearance, orhyperemic spot) which, can be quite unsightly; 2) skin atrophy orthinning of the skin; and 3), mask an infection or suppress the hostresponse to invasion by opportunistic pathogens.

This latter point is of great importance in any dermatological disorderthat may result in an open lesion. Open lesions are a notoriouslyfavorable environment for opportunistic infection. The warmth, bloodsupply, pH, and necrotic tissue are all conducive to bacterial or fungalcolonization. Using a steroid in this environment may slow the responseto an infection and thereby mask commonly observed and treated signs andsymptoms of an infection; namely, purulence or puss. Thus, a simpleinfection in the presence of a topical steroid can be masked to thepoint of serious infection or even sepsis.

Reduced killing of pathogens is a detrimental consequence of therapywith anti-infammatory drugs. In addition to α MSH's and/or itsderivatives potent anti-inflammatory effects, a MSH and/or itsderivatives shows anti-microbial efficacy as well. It has been shownthat the influences of αMSH and/or its derivatives on common skinpathogens, i.e. Staphylococcus Aureus and Candida Albicans, showedbactericidal and fungicidal properties. See, Cutull, Cristiani, Liptonand Catania, Antimicrobial Effects of α MSH Peptides, Journal ofLeukocyte Biology, Volume 67, February 2000.

It follows that the use of a preparation that could offer all thebenefits of steroid preparations, antipyretics, analgesics, andantihistamines but without the attendant side effects, will be a greataddition to the available avenues of treatment of these types ofsymptoms and these types of disorders.

SUMMARY OF THE INVENTION

The present invention is directed to a treatment for dermatologicaldisorders and a method for preventing dermatological disorders and theirassociated symptomatolgy. One aspect of this invention involves adermatological treatment comprising one or more polypeptides with anamino acid sequence including KPV (SEQ. ID. NO. 1), MEHFRWGKPV (SEQ. ID.NO. 2), HFRWGKPV (SEQ. ID. NO. 3), or SYSMEHFRWGKPV (SEQ. ID. NO. 4) forthe treatment of the cutaneous sequelae associated with dermatologicaldisorders. The polypeptides are at a level to effectively treat thecutaneous inflammation, edema, erythema, opportunistic infection andpruritis, and are dissolved into a carrier.

The one or more polypeptides can also be a dimer formed from any of theamino acid sequences above. In one preferred embodiment of theinvention, the one or more polypeptides are dissolved in an appropriatecarrier and are used to cure or ameliorate the sequelae ofdermatological disorders. In another preferred embodiment, the carrierhas its own medicinal and/or palliative properties. In another preferredembodiment of the invention, the one or more polypeptides are dissolvedin a liquid that is associated with an absorbent material forapplication on the skin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a representation of the chemical structure of one form ofthe KPV dimer for use with one aspect of the invention.

GENERAL DESCRIPTION OF THE INVENTION

The references cited above and below are incorporated by reference as iffully set forth herein. The present invention involves a treatment forcuring dermatological disorders, methods of treatment of the sequelae ofdermatological disorders when they have manifested, and prevention ofoutbreaks or manifestations in dermatological disorders with the use ofalpha-melanocyte stimulating hormone (“□-MSH”) and/or its derivatives.

α-MSH is an ancient thirteen amino-acid peptide (SEQ. ID. NO. 4)produced by post-translational processing of the larger precursormolecule propiomelanocortin. It shares the 1-13 amino acid sequen cewith adrenocorticotropic hormone (“ACTH”), also derived frompropiomelanocortin. α-MSH is known to be secreted by many cell typesincluding pituitary cells, monocytes, melanocytes, and keratinocytes. Itcan be found in the human epidermis, the skin of rats or in the mucosalbarrier of the gastrointestinal tract in intact and hypophysectomizedrats. See e.g. Eberlie, A. N., The Melanotrophins, Karger, Basel,Switzerland (1998); Lipton, J. M., et al., Anti-inflammatory Influenceof the Neuroimmunomodulator α-MSH, Immunol. Today 18, 140-145 (1997);Thody, A. J., et al., MSH Peptides are Present in Mammalian Skin,Peptides 4, 813-815 (1983); Fox, J. A., et al., Immunoreactiveα-Melanocyte Stimulating Hormone, Its Distribution in theGastrointestinal Tract of Intact and Hypophysectomized Rats, Life. Sci.18, 2127-2132 (1981).

α-MSH and/or its derivatives are known to have potent antipyretic,anti-inflammatory properties and antifungal and antibiotic effects; yetthey have extremely low toxicity. They can reduce production of hostcells' proinflammatory mediators in vitro, and can also reduceproduction of local and systemic reactions in animal models forinflammation. The “core” α-MSH sequence (4-10) (SEQ. ID. NO. 2), forexample, has learning and memory behavioral effects but littleantipyretic and anti-inflammatory activity. In contrast, the activemessage sequence for the antipyretic and anti-inflammatory activitiesresides in the C-terminal amino-acid sequence of α-MSH, that is,lysine-proline-valine (“Lys-Pro-Val” or “KPV”) (SEQ. ID. NO. 1). Thistripeptide has activities in vitro and in vivo that parallel those ofthe parent molecule.

The anti-inflammatory activity of α-MSH and/or its derivatives isdisclosed in the following patents which are hereby incorporated byreference: U.S. Pat. No. 5,028,592, issued on Jul. 2, 1991 to Lipton, J.M., entitled Antipyretic and Anti-inflammatory Lys-Pro-Val Compositionsand Method of Use; U.S. Pat. No. 5,157,023, issued on Oct. 20, 1992 toLipton, J. M., entitled Antipyretic and Anti-inflammatory Lys-Pro-ValCompositions and Method of Use; see also Catania, A., et al.,α-Melanocyte Stimulating Hormone in the Modulation of Host Reactions,Endocr. Rev. 14, 564-576 (1993); Lipton, J. M., et al.,Anti-inflammatory Influence of the Neuroimmunomodulator of α-MSH,Immunol. Today 18, 140-145 (1997); Rajora, N., et al., α-MSH ProductionReceptors and Influence on Neopterin, in a Human Monocyte/macrophageCell Line, J. Leukoc. Biol. 59, 248-253 (1996); Star; R. A., et. al.,Evidence of Autocrine Modulation of Macrophage Nitric Oxide Synthase byα-MSH, Proc. Nat'l. Acad. Sci. (USA) 92, 8015-8020 (1995); Lipton, J.M., et al., Anti-inflammatory Effects of the Neuropeptide α-MSH in AcuteChronic and Systemic inflammation, Ann. N.Y. Acad. Sci. 741, 137-148(1994); Fajora, N., et al., α-MSH Modulates Local and Circulating TumorNecrosis Factor α in Experimental Brain Inflammation, J. Neuroosci, 17,2181-2186 (1995); Richards, D. B., et al., Effect of α-MSH (11-13)(lysine-proline-valine) on Fever in the Rabbit, Peptides 5, 815-817(1984); Hiltz, M. E., et al., Anti-inflammatory Activity of aCOOH-terminal Fragment of the Neuropeptide α-MSH, FASEB J. 3, 2282-2284(1989).

In a preferred embodiment of the invention, these anti-inflammatoryactivities are most particularly associated with the C-terminalamino-acid sequence—KPV. This tripeptide, along with □-MSH and/or itsderivatives, are effective over a very broad range of concentrations,including picomolar concentrations that normally occur in human plasma.

As discussed in the background section, a topical treatment fordermatological disorders is desired. For treatment of these conditions,α-MSH and/or its derivatives can be applied to the affected areas bymethods known in the art. For example, α-MSH and/or its derivatives canbe dissolved in solutions such as a phosphate buffer saline,hyalurinate, methylcellulose, carboxymethlcellulose, or ethanol. Commoncarriers such as cream, ointment, balm, aerosol foam, aerosol spray,pump spray, gel, stick, liquid, or absorbent material can carry α-MSHand/or its derivatives as active ingredients for treating dermatologicaldisorders. These carriers can be applied to the affected portion of theintegument by spray, absorbent material wipes, swabs or any of a numberof applicators known in the art, bandages, or fingers.

More specifically, one preferred embodiment of the invention is todissolve α-MSH and/or its derivatives in an ointment, cream, lotion,balm, aerosol foam, aerosol spray, pump spray, gel, stick, or liquidcarrier. The carrier containing the solvated α-MSH and/or itsderivatives may have palliative properties in and of themselves, i.e.lanolin an emollient or white petroleum as a moisturizing agent.Additionally, the α-MSH and/or its derivatives can be combined with acarrier and another chemical with medicinal properties of its own, i.e.hydrocortisone cream. The resulting combination can be topically appliedto the skin.

Another preferred embodiment of the invention is a treatment packet witha wipe made of absorbent material that is treated with α-MSH and/or itsderivatives that have been dissolved into a liquid-based carrier. Theprocess for making wipes of absorbent material is well known in the art.For example, baby wipes, moist towelettes, make-up removal cloths, andalcohol swabs are all wipes of absorbent material. Commercial examplesof such wipes include CHUBS® Baby Soft Wipes, DEXUS® Antibacterial HandWipes, DEXUS® Makeup Remover Wipes, TINACTIN® Sports Wipes for Athlete'sFoot, and B-D® Alcohol Swabs. Treatment of the wipe's absorbent materialis accomplished by first soaking the absorbent material in a solution ofα-MSH and/or its derivatives. The wipe remains in a liquid-impermeablepackaging until use, when the package is opened and the wet wipe isapplied to the affected portion of the integument. The processes formaking liquid-impermeable packages are well known in the art. Forexample, packages made of layers of paper, metal foil, and metal foilcoated paper are commonly used for packaging wipes of absorbentmaterial. For example, moist towelettes, such as MASSENGILL® FeminineCleansing Soft Cloth Towelettes, and alcohol swabs, such as B-D® AlcoholSwabs, are packaged in this manner.

In another embodiment of the invention, α-MSH, and/or its derivatives,may be administered parenterally. For this embodiment, pharmaceuticalpreparations of the tripeptide, or its derivatives, may be generallyobtained by combining the active ingredient in combination withpharmaceutically acceptable buffers, dilutents, stabilizers, and thelike. In a preferred composition, approximately 100 to 500 mg of theactive ingredient is dispersed into about 1-7 ml of sterile, isotonicsaline, including a pharmacologically accepted buffer to maintain pH atabout neutral. Parenteral administration may be desired when a diseasemanifests a pronounced dermatological involvement, i.e. erythemamultiforme.

Additionally, due to its small size, membrane permeability andrelatively acid-stable structure, it will be recognized that the α-MSH,and/or its derivatives, may be administered orally, through theoropharanx or nasopharanx via an appropriate inhalant apparatus oranally with the use of a suppository.

Pharmacologically effective concentrations of these peptides may beincorporated into commercial formulations of ointments, creams, gels,parenterals, tablets, or atomized sprays.

Formulations of creams and gels are well known in the art. HARRY'SCOMSETICOLOGY (Chemical Publishing, 7^(th) ed. 1982); REMINGTON'SPHARMACEUTICAL SCIENCES (Mack Publishing Co., 18^(th) ed. 1990).

Set forth below are examples of various formulations of the invention.As used below the term “Active Ingredient” refers to one or morepeptides selected from the group of peptides with a C-terminal sequenceconsisting of KPV, HRFWGKPV and SYSMEHFRWGKPV. Preferably, the activeingredient is KPV or VPK-Ac-CC-Ac-KPV.

An exemplary parenteral preparation comprises:

Sterile Isotonic Saline 1–7 cc Pharmaceutically Accepted In an amountadequate to Buffer maintain pH of about neutral Active Ingredient100–500 mg

An exemplary formulation of a gel based on the invention comprises:

Propylene Glycol 100.0 g PEG-Glyceryl Cocoate 100.0 g di-α-Tocopherol  .2 g Ascorbyl Palmitate   10 g Propyl Gallate  .02 g Citric Acid,annhydr   .1 g Isopropanol   500 g Hydroxypropyl Methyl Cellulose   30 gWater  1000 g Active Ingredient 8 g–86 g (i.e. 8 g for ½%, 86 g for 5%gel)

An exemplary formulation of a cream comprises:

Glycerol    50 g Na₂-EDTA   .3 g Glycerides   100 g Cetyl Alcohol    10g Stearyl Alcohol    10 g Glycerol mono Stearate    40 g Cetereth    20g di-α-tocopherol   .2 g Water 1000.0 g Active Ingredient 6 g–62 g (i.e.6 g for ½%; 62 g for 5% cream)

An exemplary formulation of an absorption base ointment comprises:

Cholesterol  30 g Stearyl Alcohol  30 g. White Wax  80 g WhitePetrolatum 860 g Active Ingredient 5–50 g (i.e. 5 g for ½%, 50 g for 5%ointment)

An example of a water removable ointment comprises:

Methylparaben 0.25 g Propylparaben 0.15 g Sodium Lauryl Sulfate   10 gPropylene Glycol  120 g Stearyl Alcohol  250 g White Petrolatum  250 gPurified Water  370 g Active Ingredient .5 g–50 g (i.e. .5 g for ½%; 50g for 5% Ointment

An exemplary formulation of a hard gelatinous tablet comprise's:

Gelatine Bloom 30  70.0 mg Maltodextrin MD 05 108.0 mg di-α-tocopherol 2.0 mg Sodium ascorbate  10.0 mg Microcrystalline cellulose  48.0 mgMagneisum stearate  2.0 mg Active Ingredient .2 * 10⁻⁹–.2 * 10⁻¹³ mg

An exemplary formulation of a hard tablet comprises:

Annhydrous lactose 130.5 mg Microcrystalline cellulose  80.0 mgdi-α-tocopherol  2.0 mg Sodium ascorbate  10.0 mg PolyvinylpyrrolidoneK30  5.0 mg Magnesium stearate  2.0 mg Active Ingredient .2 * 10⁻⁹–.2 *10⁻¹³ mg

As mentioned, topical administration may be made with manual applicationof creams, ointments, gels, or with an atomized spray. Systemicadministration may be made by ingestion of hard tablets, soft tablets orcapsules or by parenteral administration.

In one preferred embodiment of the invention a therapeutically effectiveamount αMSH and/or its derivatives is used in combination with ananti-inflammatory agent selected from the group consisting ofbeclomethasone diprorionate, betamethasone, cortisone, dexamethasone,flucionide, hydrocortisone, methylprednisolone, prednisolone,prednisone, and triamcinolone. The forgoing glucocorticoids may beexchanged in another preferred embodiment of the invention fornon-steroidal anti-inflammatory agents selected from the groupconsisting of aspirin, diflusinal, fenoprophen calcium, ibuprofen,indomethacin, meclofenamate sodium, naproxen, phenylbutazone, piroxicam,sulindac, and tolmetin sodium.

In yet another preferred embodiment of the invention these peptides areused in combination with a therapeutically effective amount of afungicide selected from the group consisting of: itraconazole,econazole, ketoconazole, miconazole and fluconazole. In yet anotherpreferred embodiment of the invention these peptides are used incombination with a therapeutically effective amount of a gram positiveor gram negative antibiotics selected from the group consisting of:aminglycosides, amoxicillin, ampicillin, azithromycin, erythromycin,nafcillin, penecillin, quinupuristin dalfopristin and vancomycin.

The following examples demonstrate the application of α-MSH and itsderivatives to treat dermatological disorders.

EXAMPLE I KPV Equivalents

This example illustrates the biological functional equivalents of α-MSHand/or its derivatives. Although specific amino acid sequences describedhere are effective, it is clear to those familiar with the art thatamino acids can be substituted or deleted without altering theeffectiveness of the peptides. Further, it is known that stabilizationof the α-MSH and/or its derivatives' sequence can greatly increase theactivity of the peptide and that substitution of D-amino acid forms forL-forms can improve or decrease the effectiveness of the peptides. Forexample, a stable analog of α-MSH, [Nle⁴,D-Phe⁷]-α-MSH, which is knownto have marked biological activity on melanocytes and melanoma cells, isapproximately ten times more potent than the parent peptide in reducingfever. Further, adding amino acids to the C-terminal of α-MSH(11-13)(SEQ. ID. NO. 1) sequence can reduce or enhance antipyretic potency.Addition of glycine to form the 10-13 sequence (SEQ. ID. NO. 5),slightly decreased potency; the 9-13 sequence (SEQ. ID. NO. 6) wasalmost devoid of activity, whereas the potency of the 8-13 sequence(SEQ. ID. NO. 7) was greater than that of the 11-13 sequence (SEQ. ID.NO. 1). It is known that Ac-[D-K11]-α-MSH 11-13-NH2 has the same generalpotency as the L-form of the tripeptide α-MSH (11-13) (SEQ. ID. NO. 1).However, substitution with D-proline in position 12 of the tripeptiderendered it inactive. see e.g. Holdeman, M., et. al., AntipyreticActivity of a Potent α-MSH Analog, Peptides 6, 273-5 (1985). Deeter, L.B., et. al., Antipyretic Properties of Centrally Administered α-MSHFragments in the Rabbit, Peptides 9, 1285-8 (1989). Hiltz, M. E.,Anti-inflammatory Activity of α-MSH (11-13) Analogs: Influences ofAlterations in Stereochemistry, Peptides 12, 767-71 (1991).

Biological functional equivalents can also be obtained by substitutionof amino acids having similar hydropathic values. Thus, for example,isoleucine and leucine, which have a hydropathic index +4.5 and +3.8,respectively, can be substituted for valine, which has a hydropathicindex of +4.2, and still obtain a protein having like biologicalactivity. Alternatively, at the other end of the scale, lysine (−3.9)can be substituted for arginine (−4.5), and so on. In general, it isbelieved that amino acids can be successfully substituted where suchamino acid has a hydropathic score of within about +/−1 hydropathicindex unit of the replaced amino acid. See, U.S. Pat. No. 5,157,023issued to James M. Lipton issued on Oct. 20, 1992.

Furthermore, these modified analogs of α-MSH and/or its derivatives canalso form dimers as exemplified by the KPV dimer in FIG. 1.

EXAMPLE II Use of KPV in Treatment of Psoriasis

In a subject with a diagnosed and confirmed greater than ten yearhistory of dermatologically symptomatic psoriasis, KPV was used to treatinflammation, scaling, dryness, pain, erythema, and pruritis. Thesubject had psoriatic lesions located bilaterally on the volar (palmside) surface of the forearms. The lesions varied in time of existencefor greater than ten years with variagated presentation. The subjectpresented no opportunistic infection of the integument secondary to thepsoriatic lesions.

KPV in a crystalline form was prepared as disclosed in U.S. Pat. No.5,028,592. Mineral oil was chosen as a carrier for the KPV preparation.One milligram of KPV was administered topically on the affected areas ofthe integument at a frequency of twice daily. For comparison purposes, astandard dosage amount of Hydrocortisone was placed on the contralateralarea of the body of the subject that also manifested the dermatologicalsequelae of psoriasis. Topical administration was accomplished withstandard cotton tipped applicators.

Symptoms associated with the psoriatic lesions showed marked improvementwithin minutes of administration. Similarly, the side treated withHydrocortisone showed improvement. The lesions treated withHydrocortisone controlled symptoms for a period of three hours whereasthe KPV treated side showed a relief from symptoms for at least eighthours. Symptoms remained limited with KPV applications every day.

This treatment was continued for eleven days. No adverse reactions orside effects were witnessed with the KPV treated side. However, thecontralaterally treated Hydrocortisone side showed telangictasia andatrophy of skin, which are known in the art to be associated withcontinued topical steroid use.

This example shows that the simple topical application of KPV in anappropriate vehicle or carrier has a therapeutic effect on psoriaticlesions that is similar in efficaciousness to an accepted standbytreatment; steroid treatment. But KPV is free of many of the unwantedside effects of steroid treatment. This means that one could use KPV foran extended period of time without risking the unwanted complications oflong term steroid therapy. One significant advantage is the eliminationof the role topical steroids play in secondary infection of the skin.

As mentioned above, psoriasis may create open lesions as well as thosetypically associated with an outbreak. Opportunistic skin pathogens,Staphylococcus Aureus, Pityrosporon sp. or Tricophyton rubrum, maysecondarily infect these open lesions. It is well known that steroidtherapy has a tendency to “mask infection” by suppressing the hostresponse to infection. Although the suppression of the inflammatoryresponse is desirable for the reduction of pain, edema and erythema, theinflammatory response is integral to the host defense mechanism againstinfection. Steroids used alone may ameliorate the symptoms associatedwith inflammation but may allow an infection to go unnoticed and tobecome serious and, in systemic infection, be life threatening. KPV hasbeen show to have both antibacterial and antifungal properties andtherefore does not present the same risk of masking an infection.

EXAMPLE III Use of KPV in Contact Dermatitis

This example illustrates the use of KPV in a subject suffering from atype of dermatitis within the class of Eczematous Dermatitis. This type,contact dermatitis, appeared to be the result of contact with leatherfrom a watchband, i.e. leather, was the primary irritant. The subjecthad been using the particular watchband for 8 months and had noticed atype of rash and pruritis that had developed six months after repeatedexposure to the watchband and had continued to worsen with use of thewatchband.

Clinically, the subject presented with poorly outlined patches oferythema that included closely grouped vesicles and evidence ofexcoriation, all of which are indicative of an acute presentation ofthis type of delayed hypersensitivity reaction. There was no evidence ofsecondary infection of open wounds or cellulitis.

The subject was given a preparation of KPV as described above in ExampleI. Marked improvement was noted within minutes of treatment and symptomsdid not return.

Contact dermatitis in its acute, subacute and chronic types can lead tosecondary infection. As mentioned above, while topical steroids mayalleviate the symptoms associated with contact dermatitis, they may alsomask a possible infection. Thus, α-MSH and/or its derivativespreparations, have uses and advantages over and above current methods.

The preceding examples demonstrate the application of α-MSH and/or itsderivatives for dermatological uses in both treatment and prevention.These are only examples and are not intended to limit the invention tothese examples. It is understood that modifying the examples above doesnot depart from the spirit of the invention. It is further understoodthat the examples can be applied on their own or in combination witheach other. Although the examples above include uses in psoriasis anddelayed hypersensitivity reactions, many other dermatological disordersshare the same sequelae as those disclosed. For example, atopicdermatitis, also within the class of eczematous dermatitis, presentswith scaling, pruritis and a vesicular-type rash. Similarly, seborrheicdermatitis presents with symptoms very much like most of the psoriaticdisorders.

1. A pharmaceutical composition comprising: a) a therapeutically effective amount of a peptide selected from the group consisting of a KPV (SEQ ID NO: 1) polypeptide and the KPV dimer; b) a therapeutically effective amount of an non-steroidal anti-inflammatory agent; and c) wherein the pharmaceutical composition is used for contact dermatitis.
 2. The pharmaceutical composition of claim 1 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin, diflusinal, fenoprophen calcium, ibuprophen, indomethacin, meclofenamate sodium, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin sodium.
 3. The pharmaceutical composition of claim 2 further comprising a carrier.
 4. The pharmaceutical composition of claim 3 wherein the carrier is selected from the group consisting a cream, an ointment, a balm, a foam, a gel, a stick, and a liquid.
 5. The pharmaceutical composition of claim 4 wherein the carrier has its own medicinal properties.
 6. The pharmaceutical composition of claim 5 wherein the medicinal properties are selected from the group consisting of emollient properties, analgesic properties, anti-pruritic properties, and soothing properties or combinations thereof.
 7. The pharmaceutical composition of claim 1 wherein the polypeptide is at a concentration of at least 0.2×10⁻⁹ mg.
 8. The pharmaceutical composition of claim 7 wherein the polypeptide is at a concentration of at least 0.2×10 ⁻¹³ mg.
 9. A pharmaceutical composition comprising: a) a therapeutically effective amount of a peptide selected from the group consisting of a KPV (SEQ ID NO: 1) polypeptide and the KPV dimer; b) a therapeutically effective amount of an non-steroidal anti-inflammatory agent; and c) wherein the pharmaceutical composition is used for psoriasis.
 10. The pharmaceutical composition of claim 9 wherein the non-steroidal anti-inflammatory drug is selected from the group consisting of aspirin, diflusinal, fenoprophen calcium, ibuprophen, indomethacin, meclofenamate sodium, naproxen, phenylbutazone, piroxicam, sulindac, and tolmetin sodium.
 11. The pharmaceutical composition of claim 10 further comprising a carrier.
 12. The pharmaceutical composition of claim 11 wherein the carrier is selected from the group consisting a cream, an ointment, a balm, a foam, a gel, a stick, and a liquid.
 13. The pharmaceutical composition of claim 12 wherein the carrier has its own medicinal properties.
 14. The pharmaceutical composition of claim 13 wherein the medicinal properties are selected from the group consisting of emollient properties, analgesic properties, anti-pruritic properties, and soothing properties or combinations thereof.
 15. The pharmaceutical composition of claim 9 wherein the polypeptide is at a concentration of at least 0.2×10⁻⁹ mg.
 16. The pharmaceutical composition of claim 15 wherein the polypeptide is at a concentration of at least 0.2×10⁻¹³ mg. 